Primary outcome: percentage of lesions cured after the end of treatment

An RCT from Pakistan compared intralesional meglumine antimoniate (ILMA) weekly versus fortnightly, until complete cure or up to eight weeks (Mujtaba 1999). Two months after treatment, 92% (102/111) of the lesions were cured in the weekly, and 85.6% (89/104) in the fortnightly group. There was no statistical difference between weekly and fortnightly administration (risk ratio (RR) 1.07, 95% confidence interval (CI) 0.98 to 1.18; N = 215; 1 study, Analysis 1.1).

Secondary outcome: speed of healing (time taken to be 'cured')

Most lesions had healed at six weeks in both groups with minimal or absent scarring.

Secondary outcome: adverse effects

Authors did not report adverse effects in any of the participants, except transient pain at the site of the injections in both groups.

Primary outcome: percentage of lesions cured after the end of treatment

One RCT from Saudi Arabia compared ILMA every other day versus IMMA 6 days a week, over a 30‐day period until the lesions had blanched (Alkhawajah 1997). The authors reported a comparable cure rate: 68.6% (48/70) and 59.7% (46/77) of the of lesions in the respective groups at the end of the treatment period (RR 1.15, 95% CI 0.90 to 1.46; N = 147; 1 study, Analysis 2.1).

Secondary outcome: adverse effects

Regarding adverse effects, both groups reported pain at the site of injection, but it was greater in the ILMA group.

Primary outcome: percentage of lesions cured after the end of treatment

An RCT from Syria compared IMMA 60 mg/kg/d plus placebo versus IMMA 30 mg/kg/d plus placebo or cimetidine for three weeks (Shanehsaz 2015). Three months after treatment, 91.1% (82/90) of the lesions were cured in the IMMA 60 mg plus placebo group, 84.6% (127/150) in the IMMA 30 mg plus cimetidine group, and 78.3% (94/120) in IMMA 30 mg plus placebo group. We did not find any significant differences in cure rates between the IMMA 30 mg plus cimetidine group versus the IMMA 30 mg plus placebo group (RR 1.08, 95% CI 0.96 to 1.21; N = 270; 1 study, Analysis 3.1) or between the IMMA 30 mg plus cimetidine group versus the IMMA 60 mg group (RR 0.93, 95% CI 0.85 to 1.02; N = 240; 1 study, Analysis 4.1). Cure rates were significantly higher in the IMMA 60 mg group compared with the IMMA 30 mg plus placebo group (RR 1.16 95% CI 1.04 to 1.30; N = 210; 1 study, Analysis 5.1).

Primary outcome: percentage of participants with a complete cure after the end of treatment

A pooled analysis of two trials showed that cure rates in the IMMA 60 mg group were better than in the IMMA 30 mg plus placebo group (RR 0.83, 95% CI 0.71 to 0.96; N = 148; Nilforoushzadeh 2008; Shanehsaz 2015, Analysis 6.1). We assessed the certainty of evidence as low, which means we are uncertain whether there is much difference in cure rate between these two concentrations of IMMA.

An RCT from Iran compared IMMA 60 mg/kg/d plus placebo versus IMMA 30 mg/kg/d plus placebo or omeprazole for three weeks (Nilforoushzadeh 2008). Three months after treatment, there was complete cure in 93% (40/43) of participants in the IMMA 60 mg plus placebo group, 89% (32/36) in the IMMA 30 mg plus omeprazole group, and 80% (36/45) in the IMMA 30 mg plus placebo group. There were no significant differences in cure rates in any comparisons: IMMA 30 mg plus omeprazole versus IMMA 60 mg (RR 0.96, 95% CI 0.83 to 1.10; N = 79; 1 study, Analysis 7.1), IMMA 30 mg plus placebo versus IMMA 60 mg plus placebo (RR 0.86, 95% CI 0.73 to 1.02; N = 88; 1 study, Analysis 8.1), or IMMA 30 mg plus omeprazole versus IMMA 30 mg plus placebo (RR 1.11, 95% CI 0.92 to 1.34; N = 81; 1 study, Analysis 9.1).

Secondary outcome: adverse effects

Regarding adverse effects, Shanehsaz 2015 reported serious adverse effects in 83.3% (n = 25) participants in the IMMA 60 mg dose group and 60% (n = 18) participants in the IMMA 30 mg group; 40% (n = 12) of participants in the IMMA 60 mg dose group and 23.3% (n = 7) in the 30 mg group experienced skin hypersensitivity, while there were five and three cases, respectively, of cardiac toxicity (QT prolongation) (Analysis 6.2). Hence, there were fewer serious adverse effects (RR 0.72, 95% CI 0.52 to 1.00; N = 60, 1 study), fewer skin reactions (RR 0.58, 95% CI 0.27 to 1.28; N = 60, 1 study), and less QT prolongation (RR 0.60, 95% CI 0.16 to 2.29; N = 60, 1 study) in the IMMA 30 mg plus placebo group, but none of the results were significant.

In Nilforoushzadeh 2008, the authors reported one case of anaphylactic shock to meglumine antimoniate (not described).

Primary outcome: percentage of lesions cured after the end of treatment

One RCT from Iran compared weekly injections of ILMA for 6 weeks alone versus ILMA at the same dose plus silver or non‐silver dressing (Khatami 2013). We performed an ITT analysis considering the lesions allocated in each arm at the beginning of the study: 26 participants with 45 lesions in the ILMA‐alone group, 31 participants with 60 lesions in the ILMA plus silver dressing group, and 26 participants with 53 lesions in the ILMA plus non‐silver dressing group. At one month after treatment, 35.5% (16/45) of lesions were cured in the ILMA‐alone group, 33.3% (20/60) in the ILMA plus silver dressing group, and 35.8% (19/53) in the ILMA plus non‐silver dressing group. There were no significant differences in cure rates between groups: ILMA plus non‐silver dressing versus ILMA alone (RR 1.01, 95% CI 0.59 to 1.72; N = 98, Analysis 10.1); ILMA plus silver dressing versus ILMA alone (RR 0.94, 95% CI 0.55 to 1.60; N = 105, Analysis 11.1); or ILMA plus silver dressing versus ILMA plus non‐silver dressing (RR 0.93, 95% CI 0.56 to 1.54; N = 113, Analysis 12.1).

Secondary outcome: adverse effects

Regarding adverse effects, participants reported itching and burning in 7.5% (n = 3) of lesions in ILMA alone group, 10.9% (n = 6) of lesions in the ILMA plus silver group, and 17.7% (n = 8) lesions in the ILMA plus non‐silver group; there was also oedema in 12.5% (n = 5), 7.2% (n = 4), and 6.6% (n = 3) of the lesions, respectively. One lesion in each group showed exudation, and another lesion was accompanied by dermatitis in the ILMA plus non‐silver group. There were no significant differences in any adverse effects rates in any comparison (Analysis 10.2; Analysis 10.3; Analysis 11.2; Analysis 11.3; Analysis 12.2; Analysis 12.3).

Primary outcome: percentage of participants with a complete cure after the end of treatment

One RCT from Iran compared ILMA (weekly injections for six weeks) plus gel mask twice a day with ILMA (weekly injections for six weeks) plus placebo (Mostafavi 2013). At the end of treatment, 75% (15/20) and 65% (13/20) of participants, respectively, had complete cure. There were no significant differences in cure rates between groups (RR 1.15, 95% CI 0.77 to 1.74; N = 40; 1 study, Analysis 13.1).

Secondary outcome: adverse effects

Regarding adverse effects, none of the participants from either group suffered severe adverse effects such as local irritation or pruritus.

Primary outcome: percentage of lesions cured after the end of treatment

An RCT from Iran compared ketoconazole 200 mg three times daily for four weeks plus intralesional sodium stibogluconate (ILSSG) (100 mg/mL on days 1, 3, and 5) versus intralesional plus intramuscular sodium stibogluconate (20 mg/kg/d intralesionally on days 1, 3, and 5, and 80 mg/kg/d intramuscularly simultaneously) versus ILSSG alone (100 mg/mL on days 1, 3, and 5) (El‐Sayed 2010). The authors reported that two months after treatment, 92.3% (12/13), 93.3% (14/15), and 58.3% (7/12) of lesions were cured in the respective groups. There were no significant differences between intralesional plus intramuscular SSG versus ILSSG alone (RR 1.60, 95% CI 0.97 to 2.63; N = 27; 1 study, Analysis 14.1).

Primary outcome: percentage of participants with a complete cure after the end of treatment

An RCT from Afghanistan compared ILSSG (five injections of 2 mL to 5 mL every 5 to 7 days, depending on lesion size) for up to 29 days versus intramuscular sodium stibogluconate (IMSSG) (20 mg/kg/d for 21 days) (Reithinger 2005). Two months after treatment, 47.3% (70/148) and 18% (26/144) of participants had complete cure in the ILSSG and IMSSG groups, respectively (RR 2.62, 95% CI 1.78 to 3.86; N = 292; 1 study, Analysis 15.1).

Secondary outcome: speed of healing (time taken to be 'cured')

In Reithinger 2005, the speed of healing took a median of 75 days in the ILSSG group and 100 days or more for the IMSSG group (the original paper reported that the time to cure was significantly shorter for participants treated with thermotherapy; P = 0.003, by the log‐rank test).

Secondary outcome: adverse effects

Regarding adverse effects, Reithinger 2005 reported that one participant experienced bradycardia and one an undefined local reaction in the ILSSG group. In the IMSSG group, one participant reported bradycardia, one tachycardia, and one palpitation. There were no significant differences in adverse effects rates between groups (RR 0.32, 95% CI 0.03 to 3.08; N = 292; 1 study, Analysis 15.2). In El‐Sayed 2010, all participants from ILSSG group suffered pain and swelling at the intralesional site, which calmed on its own within two days. IMSSG was associated with pain at the injection site.

Primary outcome: percentage of participants with a complete cure after the end of treatment

An RCT from Kuwait compared oral ketoconazole at 600 mg/d versus 800 mg/d for six weeks or until the participant was cured, whichever occurred earlier (Alsaleh 1995). The authors reported that at the end of treatment, 66.7% (12/18) and 60% (9/15) of participants in the respective groups had a complete cure (RR 1.11, 95% CI 0.66 to 1.88; N = 33; 1 study Analysis 16.1). Thereafter, investigators followed up participants every one to two months for a period of six months, with no change.

Secondary outcome: adverse effects

None of the participants from either group relapsed during a six‐month follow‐up. With regard to adverse effects, one participant had nausea and vomiting in the ketoconazole 800 mg/d group. There were no significant differences in adverse effects rates between groups (RR 0.28, 95% CI 0.01 to 6.43; N = 33; 1 study, Analysis 16.2).

Primary outcome: percentage of participants with a complete cure after the end of treatment

An RCT from Iran compared oral ketoconazole 600 mg/d for 30 days versus six to eight injections of ILMA, biweekly (Salmanpour 2001). The authors reported that six weeks after treatment, 89% (57/64) and 72% (23/32) of participants in the respective groups had a complete cure. There were no significant differences between groups (RR 1.24, 95% CI 0.98 to 1.56; N = 96; 1 study, Analysis 17.1).

Secondary outcome: adverse effects

In the ketoconazole group the most common side effect cited was nausea and abdominal pain, and liver enzymes doubled in two participants, returning to normal two weeks after the end of treatment. There were no significant differences in adverse effects rates between groups (RR 2.54, 95% CI 0.13 to 51.36; N = 96; 1 study, Analysis 17.2). In the ILMA group, the most common side effect was redness and swelling after the injection. None of the side effects were significant enough to discontinue treatment.

Primary outcome: percentage of lesions cured after the end of treatment

An RCT from Iran compared oral ketoconazole plus ILSSG for four weeks versus ILSSG plus IMSSG versus ILSSG alone (El‐Sayed 2010). The authors reported that two months after treatment, 92.3% (12/13), 93.3% (14/15), and 58.3% (7/12) of the lesions were cured in the respective groups. There were no significant differences between comparisons of either ketoconazole plus ILSSG versus ILSSG alone (RR 1.58, 95% CI 0.96 to 2.62; N = 25; 1 study, Analysis 18.1) nor between ketoconazole plus ILSSG versus ILSSG plus IMSSG (RR 0.99, 95% CI 0.80 to 1.22; N = 28; 1 study, Analysis 19.1).

Secondary outcome: adverse effects

Regarding adverse effects, in one trial all participants complained of pain and swelling at the intralesional injection site that subsided on its own within days; no participants in the oral ketoconazole group reported adverse effects (El‐Sayed 2010).

We also found one trial comparing oral ketoconazole with topical paromomycin/MBCL (Özgöztasi 1997); we assess this comparison in the topical paromomycin section (section 3.2 below).

Primary outcome: percentage of participants with a complete cure after the end of treatment

Three RCTs compared itraconazole versus placebo and reported complete cure three months after the end of treatment as a primary outcome (Al‐Fouzan 1991; Dogra 1996; Nassiri‐Kashani 2005). Although heterogeneity was high (P = 0.02; I² = 73%), the three studies obtained results favouring itraconazole, so we decided to maintain the pool of results and the meta‐analysis (RR 3.70, 95% CI 0.35 to 38.99; N = 244; 3 studies, Analysis 22.1).

Please see summary of findings Table for the main comparison, where we assessed the certainty of evidence as very low, which means we are very uncertain about the difference in cure with itraconazole compared to placebo.

Two RCTs evaluated complete cure of participants at other time points. An RCT from Iran compared oral itraconazole for three weeks versus placebo (Momeni 1996). Fifty‐one days after treatment, results showed complete cure of participants in 51.4% (36/70) and 38.6% (27/70) of the participants, respectively. There were no significant differences in cure rates between groups (RR 1.33, 99% CI 0.82 to 2.18; N = 140; 1 study, Analysis 21.1). An RCT from India compared oral itraconazole for six weeks with placebo (Dogra 1992). At the end of the treatment period, 75% (15/20) of participants in the oral itraconazole group and 0% (0/20) of the participants in the placebo groups achieved a complete cure. There were no statistically significant differences in cure rates between groups (RR 31.00, 99% CI 0.83 to 1151.33; N = 40; 1 study, Analysis 20.1).

Secondary outcome: adverse effects

In Al‐Fouzan 1991, two participants from the itraconazole group reported nausea and headache during the course of treatment, and one participant had elevated liver enzymes that returned back to normal upon discontinuation of the drug. Dogra 1992 reported nausea in 12 cases (30%) between the itraconazole and dapsone groups. In the itraconazole group, two participants (10%) also had mildly abnormal liver function that reverted after completion of therapy. In Momeni 1996, six participants in the itraconazole group and four participants in the placebo group complained of mild abdominal pain and nausea. None of the laboratory values were outside normal limits. In Dogra 1996, one participant showed abnormal liver function and one nausea in the itraconazole group. Participants in the placebo group did not report adverse effects. In Nassiri‐Kashani 2005, the most common adverse effects were gastrointestinal complaints and headache – reported only in the itraconazole group during the follow‐up period. Participants in the placebo group reported adverse effects only during the treatment period.

Participants of itraconazole group had more side effects, including mild abdominal pain and nausea (RR 2.36, 95% CI 0.74 to 7.47; 3 studies, N = 204, Analysis 22.2) as well as mild abnormal liver function (RR 3.08, 95% CI 0.53 to 17.98; N = 84, 3 studies, Analysis 22.2). However, the very low certainty of the evidence means we are uncertain about these results (summary of findings Table for the main comparison).

Tertiary outcomes: microbiological or histopathological cure of skin lesions

In Dogra 1996, parasitological cure was significantly higher (Fisher's exact test P = 0.048) in participants receiving itraconazole compared to placebo. Parasitological cure occurred in 80% (8/10) of itraconazole‐treated participants but in none of the participants in the placebo group at six weeks follow‐up (RR 17.0, 95% CI 0.47 to 612.21; N = 20; 1 study, Analysis 22.3).

Please see summary of findings Table for the main comparison where we assessed the certainty of evidence.

Primary outcome: percentage of participants with a complete cure after the end of treatment

An RCT from India compared oral itraconazole 200 mg/d for six weeks versus no treatment (Dogra 1990). The authors reported complete cure of participants in 66.7% (10/15) of the treatment group but in none of the no treatment group. Low statistical power meant that these differences could have been due to chance (RR 7.88, 99% CI 0.23 to 265.70; N = 20; 1 study, Analysis 23.1).

Secondary outcomes: duration of remission and percentage of people with treated lesions that recur within six months, one year, two years, and three years

Participants responding to therapy had no relapses at three‐month follow‐up.

Secondary outcome: adverse effects

Regarding adverse effects, the drug was generally well tolerated, although 20% (3/15) of participants in the itraconazole group reported mild headache and dizziness. There were no significant differences in adverse effects rates between groups (RR 2.63, 95% CI 0.16 to 43.63; N = 20; 1 study, Analysis 23.2).

Tertiary outcomes: microbiological or histopathological cure of skin lesions

At six weeks, 66.7% (10/15) of the participants in the itraconazole group were free of parasites. Untreated participants were still parasitologically active. Low statistical power meant that these differences could have been due to chance (RR 7.88, 95% CI 0.54 to 114.56; N = 20; 1 study, Analysis 23.3).

Primary outcome: percentage of lesions cured after the end of treatment

One RCT from Aleppo, Syria compared fluconazole 200 mg/d for six weeks versus placebo (Dandashli 2005). The authors reported that at the end of treatment, 28.4% (75/264) of the lesions in the fluconazole group and 9.8% (10/102) in the placebo group had completely resolved. Cure rates were higher in the oral fluconazole group compared with placebo (RR 2.90, 95% CI 1.56 to 5.38, Analysis 24.1).

Primary outcome: percentage of participants with a complete cure after the end of treatment

One RCT from Saudi Arabia compared oral fluconazole 200 mg/d versus placebo for six weeks (Alrajhi 2002). Three months after treatment, 59% (63/106) participants in the oral fluconazole and 21% (22/103) in the placebo group had achieved complete cure (RR 2.78, 95% CI 1.86 to 4.16; N = 209; 1 study, Analysis 24.2).

Secondary outcome: speed of healing (time taken to be 'cured')

Only Alrajhi 2002 reported the speed of healing, finding that this took a median of 8.5 weeks in the fluconazole group and 11.2 weeks in the placebo group (the original paper reported that the time to cure was significantly shorter for participants treated with thermotherapy; P < 0.001, by the log‐rank test). Also, none of the participants with complete healing had a relapse during a mean follow‐up of seven months.

Secondary outcome: adverse effects

In both studies participants from reported mild and similar side effects, although the authors did not describe them (Alrajhi 2002; Dandashli 2005).

Primary outcome: percentage of participants with a complete cure after the end of treatment

One RCT from Iran compared oral fluconazole 400 mg/d versus 200 mg/d for six weeks (Emad 2011). The authors reported that at the end of treatment, 48.3% (29/60) of participants in the 200 mg group and 81% (47/58) in the 400 mg group achieved complete cure (RR 1.68, 95% CI 1.25 to 2.24; N = 118; 1 study, Analysis 25.1).

Secondary outcome: adverse effects

Regarding adverse effects, two participants in the 400 mg group discontinued treatment because of a rise of serum creatinine and liver enzymes. Participants in the 400 mg group reported 45 (75%) cases of cheilitis and 10 (16.6%) cases of nausea, compared to none in the 200 mg group (cheilitis: RR 94.08, 95% CI 5.93 to 1492.36; nausea: RR 21.71, 95% CI 1.30 to 362.21; N = 118; 1 study, Analysis 25.2).

Primary outcome: percentage of participants with a complete cure after the end of treatment

Two RCTs comparing oral dapsone versus placebo reported complete cure after the end of treatment as a primary outcome (Dogra 1991; Dogra 1992). Although heterogeneity was high (P = 0.02; I² = 73%), both studies obtained results favouring dapsone, so we decided to maintain the pool of results and meta‐analysis (RR 24.08, 95% CI 1.44 to 403.43; N = 160; 2 studies; I² = 71%, Analysis 26.1).

Secondary outcomes: duration of remission and percentage of people with treated lesions that recur within six months, one year, two years, and three years

In Dogra 1992, participants initially responding to therapy did not relapse at follow‐up, while two cases with single lesions (10%) demonstrated spontaneous healing in the placebo group at three months' follow‐up.

Secondary outcome: adverse effects

Regarding adverse effects, 30% (n = 12) of participants in the dapsone group experienced nausea. In Dogra 1991, 5% (3/60) of participants in the dapsone group developed anaemia and 15% (9/60), nausea. Nausea rates were higher in the dapsone group compared with placebo (RR 21.86, 95% CI 3.04 to 157.29; N = 160; 2 studies; I² = 0%, Analysis 26.2).

Tertiary outcomes: microbiological or histopathological cure of skin lesions

Regarding the parasitological cure, 5% (3/60) of participants in the placebo group showed healing with negative smears one month after treatment (Dogra 1991).

Primary outcome: percentage of participants with a complete cure after the end of treatment

An RCT from Iran compared oral allopurinol 15 mg/kg/d for three weeks versus IMMA 30 mg/kg/d for two weeks versus oral allopurinol 15 mg/kg/d plus IMMA 30 mg/kg/d simultaneously, using the same dosage schedule (Esfandiarpour 2002). The authors reported that 18% (9/50) of participants receiving allopurinol alone achieved complete cure, compared to 24% (12/50) in the IMMA group and 46% (23/50) in the allopurinol plus IMMA group at the end of the treatment period. The group receiving allopurinol plus IMMA had better cure rates than those receiving allopurinol alone (RR 3.83, 95% CI 1.71 to 8.60; N = 100; 1 study, Analysis 27.1) or IMMA alone (RR 1.92, 95% CI 1.08 to 3.41; N = 100; 1 study, Analysis 28.1). There was no difference regarding cure rates between the groups receiving allopurinol alone versus IMMA alone (RR 0.75, 95% CI 0.35 to 1.62; N = 100; 1 study, Analysis 29.1).

An RCT from Iran compared oral allopurinol 20 mg/kg/d plus IMMA 10 mg/kg/d versus IMMA 20 mg/kg/d alone for up to 28 days (Ejaz 2014). There was no data to address the primary outcome of percentage of participants with a complete cure.

Another RCT in an Iranian army camp compared oral allopurinol 20 mg/kg/d plus low‐dose IMMA 30 mg/kg/d for 20 days versus IMMA 60 mg/kg/d for 20 days (Momeni 2002). In this trial the authors reported that 51 days after treatment, 69% (25/36) and 72% (26/36) of participants, respectively, achieved a complete cure (RR 0.96, 95% CI 0.71 to 1.29; N = 72; 1 study, Analysis 30.1).

Secondary outcome: adverse effects

Esfandiarpour 2002 observed a few adverse effects in the allopurinol group: three participants experienced nausea and heartburn, and two saw a mild increase in serum glutamic‐oxaloacetic transaminase and serum glutamic pyruvic transaminase levels. In Momeni 2002 participants tolerated the drugs well, and only 17% (6/36) in the combined treatment group complained of mild abdominal pain and nausea; however, 3% (1/36) of participants in the IMMA group developed skin eruption, and 11% (4/36) suffered generalised muscle pain and weakness. There was no significant difference between groups in total adverse effects (Analysis 30.2). Ejaz 2014 reported secondary infection in 12.1% (n = 21) of participants in the allopurinol plus IMMA group and in 12.5% (n = 19) of participants in the IMMA group, myalgia in 5.7% (n = 10) and 7.9% (n = 12), anorexia in 7.5% (n = 13) and 5.9% (n = 9), and ECG changes in 0.6% (n = 1) and 1.98% (n = 3), respectively. In the IMMA alone group one participant suffered chest pain; two, pain at the injection site; and five, abscess. There was no significant difference regarding adverse effects rates between the two groups (Analysis 31.1).

Tertiary outcomes: microbiological or histopathological cure of skin lesions

Only one study reported that 83.3% (30/36) of participants in the allopurinol plus IMMA group and 75% (27/36) in the IMMA alone group had parasitologically free lesions one month after the end of treatment (Momeni 2002). There was no difference regarding cure rates between groups ((RR 1.11, 95% CI 0.88 to 1.41; participants = 72; studies = 1) Analysis 30.3).

Primary outcome: percentage of participants with a complete cure after the end of treatment

An RCT with participants from the Pakistani army compared oral allopurinol 20 mg/kg/d versus intravenous sodium stibogluconate (IVSSG) for 15 days (Mashood 2001). The authors reported at the end of the treatment period, 85% (17/20) of participants in the allopurinol group and 70% (14/20) in the IVSSG group achieved a complete cure. There was no significant difference regarding cure rates between groups (RR 1.21, 95% CI 0.86 to 1.71; N = 40; 1 study, Analysis 32.1).

Secondary outcome: adverse effects

Mashood 2001 observed adverse effects that included nausea, vomiting, anorexia, and diarrhoea in 5% (1/20) of participants in the allopurinol group and 20% (4/20) of participants in the IVSSG group. In the SSG group, 10% (2/20) of participants experienced liver abnormalities and 15% (3/20), myalgia and body aches. In the allopurinol group, 5% (1/20) had elevated liver enzymes, and 10% (2/20), macular rash, but there was no myalgia or body aches. There was no significant difference in adverse effects rates between the allopurinol group and IVSSG alone group (Analysis 32.2).

Primary outcome: percentage of participants with a complete cure after the end of treatment

An RCT from Saudi Arabia compared oral rifampicin 10 mg/kg/d for four to six weeks versus placebo (Jaffar 2006). Three months after treatment, 45.7% (21/46) of participants in the oral rifampicin group and 18.8% (3/16) of the placebo group achieved complete cure. There was no difference in cure rates between oral rifampicin and placebo (RR 2.43, 95% CI 0.84 to 7.08; N = 62; 1 study, Analysis 33.1).

Two RCTs from India address the primary outcome of percentage of participants with a complete cure at the end of treatment. Kochar 2000 compared 10 mg/kg/d oral rifampicin for four weeks versus placebo, reporting that 68% (17/25) and 4% (1/25) of participants, respectively, achieved complete cure by the end of the treatment period (RR 17.00, 95% CI 2.45 to 118.19; N = 50; 1 study, Analysis 33.1). Kochar 2006 compared 10 mg/kg/d oral rifampicin plus 20 mg/d omeprazole for six weeks versus placebo, reporting that 64% (16/25) participants in the rifampicin group and 12% (3/25) in the placebo group had achieved a complete cure at the end of the treatment period (RR 5.33, 95% CI 1.77 to 16.05; N = 50; 1 study, Analysis 34.1).

Secondary outcome: adverse effects

Jaffar 2006 reported that one participant had elevated liver enzymes that returned back to normal upon discontinuation of the drug. Kochar 2000 reported that the drug was very well tolerated, and there were no adverse effects during therapy.

Tertiary outcomes: microbiological or histopathological cure of skin lesions

Kochar 2000 reported an absence of parasites in 8% (2/25) and 32% (8/25) of partially healed lesions in the rifampicin and placebo groups, respectively, at the end of treatment (RR 0.25, 95% CI 0.06 to 1.06; N = 50; 1 study, Analysis 33.2).

Secondary outcome: speed of healing (time taken to be 'cured')

An RCT from Iran compared cryotherapy (liquid nitrogen via a cotton swab for 10 s to 25 s every two weeks for four weeks) plus either oral terbinafine 500 mg/d for four weeks or plus IMMA 15 mg/kg/d (Farajzadeh 2015). After three months' follow‐up, the crude hazard ratio was 0.53 (95% CI 0.30 to 0.98) and after adjustment for sex, it was 0.35 (95% CI 0.19 to 0.69). A Kaplan‐Meier analysis indicated that the difference in complete treatment between the groups was not significant.

Primary outcome: percentage of lesions with a complete cure after the end of treatment

An RCT from Iran compared azithromycin 500 mg for five days/month up to a maximum of four months with IMMA 60 mg/kg/d for 20 days (Layegh 2007). After 16 weeks of follow‐up, 10.3% (13/29) and 34.4% (20/58) of the lesions were cured in the respective groups (RR 0.60, 95% CI 0.18 to 2.01; N = 87; 1 study, Analysis 35.1).

Primary outcome: percentage of participants with a complete cure after the end of treatment

An RCT from Iran compared azithromycin 10 mg/kg/d (maximum 500 mg/d) plus allopurinol 10 mg/kg for one month versus IMMA 20 mg/kg/d for 20 days (Dastgheib 2012); 38.9% (14/36) and 40% (14/35) of participants, respectively, had achieved complete cure at two months after treatment (RR 0.97, 95% CI 0.55 to 1.73; N = 71, Analysis 36.1). There was no statistical difference in cure rates between azithromycin plus allopurinol versus IMMA in ulcerated (P = 0.40) and non‐ulcerated (P = 0.37) lesions or with regard to the site of lesions (P = 0.30).

Secondary outcome: adverse effects

Regarding adverse effects, Dastgheib 2012 reported that one (2.7%) participant in the azithromycin plus allopurinol group had gastrointestinal complaints and severe headache, and three (8.3%) experienced slight gastrointestinal complications (nausea, heartburn, and epigastric pain). Layegh 2007 described only nausea and vomiting in two participants (9%) in the azithromycin alone group. Only Dastgheib 2012 reported myalgia in two (5.7%) participants in the IMMA group. There were no significant differences in adverse effects rates between groups (Analysis 35.2; Analysis 36.2).

Primary outcome: percentage of participants with a complete cure after the end of treatment

An RCT from Iran compared oral pentoxifylline 400 mg three times daily plus IMMA 20 mg/kg/d versus IMMA 20 mg/kg/d plus placebo, for 20 days (Sadeghian 2006a). Three months after treatment, 81.3% (26/32) and 50% (16/32) of the participants in the respective groups had achieved complete cure (RR 1.63; 95% CI 1.11, 2.39, Analysis 37.1).

Secondary outcome: adverse effects

Regarding adverse effects, one participant in the IMMA plus placebo group had an allergic macule‐papular itchy rash. There were no significant differences in adverse effects rates between groups (RR 0.33, 95% CI 0.01 to 7.89; N = 64; 1 study, Analysis 37.2).

Primary outcome: percentage of participants with a complete cure after the end of treatment

An RCT in Iran compared oral miltefosine 2.5 mg/kg/d for four weeks versus IMMA 20 mg/kg/d for two weeks (Mohebali 2007). Three months after treatment, 81.3% (26/32) and 80.6% (25/31) of participants in the respective groups had achieved complete cure (RR 1.01; 95% CI 0.79, 1.28, Analysis 38.1).

An RCT from Iran compared oral miltefosine 2.5 mg/kg/d for four weeks versus IMMA 60 mg/kg/d for two weeks (Khatami 2012). At one month after treatment, 32% (10/31) and 35.7% (15/42) of the participants in the respective groups had achieved complete cure (RR 0.90, 95% CI 0.47 to 1.73; N = 73; 1 study, Analysis 39.1).

Secondary outcome: adverse effects

Mohebali 2007 did not report any relapse at six months post‐treatment. With regard to adverse effects, during the first week participants from the miltefosine group suffered from nausea, vomiting, diarrhoea, abdominal pain, and cough. Participants from the IMMA group had only diarrhoea and local pain. During the second week, participants receiving miltefosine suffered from nausea, vomiting, abdominal pain, headache, itch, and fever. Participants receiving IMMA developed those adverse effects as well as local pain, chest pain, and cough. Khatami 2012 only reported that adverse effects were higher in the miltefosine arm (nine cases versus one case).

Primary outcome: percentage of participants with a complete cure after the end of treatment

An RCT from Iraq compared oral zinc sulphate at different doses: 2.5 mg/kg/d, 5 mg/kg/d, or 10 mg/kg/d, versus no treatment (Sharquie 2001). The authors reported that 45 days after treatment, 66.7% (26/39) in the 2.5 mg/kg/d group, 73% (27/37) in the 5 mg/kg/d group, and 79% (31/39) in the 10 mg/kg/d group had achieved complete cure. In the control group, all lesions were still active at day 45. There were no significant differences in cure rates between oral zinc sulphate 2.5 mg/kg/d versus 5 mg/kg/d (RR 0.91, 95% CI 0.68 to 1.23; N = 76; 1 study, Analysis 40.1); 2.5 mg/kg/d versus 10 mg/kg/d (RR 0.84, 95% CI 0.64 to 1.10; N = 78; 1 study, Analysis 41.1); or 5 mg/kg/d versus 10 mg/kg/d (RR 0.92, 95% CI 0.71 to 1.18; N = 76; 1 study, Analysis 42.1).

Secondary outcome: speed of healing (time taken to be 'cured')

In the zinc sulphate 2.5 mg/kg/d group, the mean time taken to cure was 30.8 days (range 21 to 45): 29.96 days (range 15 to 45) in the 10 mg/kg/d group and 28.32 days (range 15 to 45) in the 10 mg/kg/d (the original paper reported that the time to cure was not statistically significant between the different treatment groups). None of the participants recovered in the control group.

Secondary outcome: prevention of scarring

In all treatment groups there was minimal or no scarring at the site of lesions.

Secondary outcome: adverse effects

Regarding adverse effects, one participant each in the 2.5 mg/kg/d, 5 mg/kg/d, and 10 mg/kg/d group had nausea and vomiting. Only one participant from the 5 mg/kg/d group had a leishmanid reaction, while two participants in the 2.5 mg/kg/d group and two from the 5 mg/kg/d group, plus one participant in the 10 mg/kg/d group, had oedema. There were no significant differences in adverse effects rates between groups (Analysis 40.2; Analysis 41.2; Analysis 42.2).

Primary outcome: percentage of participants with a complete cure after the end of treatment

An RCT from Iran compared oral zinc sulphate (ZS) in a dose of 10 mg/kg/d for 45 days versus IMMA 20 mg/kg/d for up to 20 days (Yazdanpanah 2011). The authors reported that 45 days after treatment, 30.2% (8/26) and 35.5% (26/74) of the respective groups achieved complete cure (RR 0.88, 95% CI 0.46 to 1.68; N = 100; 1 study, Analysis 43.1).

Secondary outcome: adverse effects

Regarding adverse effects, the authors did not report any adverse effects in the oral zinc sulphate group, but six participants in the IMMA group dropped out because of adverse effects, including severe erythema and pruritus at inoculation site and severe muscular pain.

Primary outcome: percentage of participants with a complete cure after the end of treatment

An RCT from Sudan compared oral artesunate plus sulphamethoxypyrazine/pyrimethamine (400 mg artesunate plus 1000 mg/50 mg sulphamethoxypyrazine/pyrimethamine for four days, four times each two weeks) versus placebo (Adam 2009). The authors reported that 72 days after treatment, 90% (18/20) and 85.7% (18/21) of the respective groups had a complete cure (RR 1.05, 95% CI 0.84 to 1.32; N = 41; 1 study, Analysis 44.1).

Secondary outcome: adverse effects

One participant in the placebo arm developed a mild skin rash with itching. There was no significant difference in biological tests (liver and renal function tests) in any of the participants before or after treatment.

Primary outcome: percentage of lesions with a complete cure after the end of treatment

An RCT from Saudi Arabia compared 2% miconazole cream twice a day with 1% clotrimazole cream twice a day for 30 days (Larbi 1995). The authors reported there was no lesions healed in the miconazole group and 15% (14/89) of the lesions healed completely in the clotrimazole group at the end of treatment (RR 0.05, 95% CI 0.00 to 0.81; N = 151; 1 study, Analysis 45.1).

Secondary outcome: adverse effects

In both treatment groups, the medication was well tolerated, with no reported adverse effects.

Primary outcome: percentage of participants with a complete cure after the end of treatment

An RCT from Iran compared topical ketoconazole versus vehicle, twice daily for 21 days (Momeni 2003). The authors reported that 51 days after treatment, 24% (11/45) and 13% (6/45) of the participants in the respective groups achieved complete cure. There were no significant differences in cure rates between topical ketoconazole and vehicle (RR 1.83, 95% CI 0.74 to 4.53; N = 90; 1 study, Analysis 46.1).

Secondary outcome: adverse effects

Regarding adverse effects, the drugs were well tolerated, and only two participants (group unknown) complained of mild pruritus at the site of the lesions.

Primary outcome: percentage of participants with a complete cure after the end of treatment

An RCT from Iran compared topical liposomal amphotericin B (3 to 7 drops twice daily) versus ILMA (maximum 2 mL) for eight weeks (Layegh 2011). We performed an ITT analysis considering the participants allocated in each arm at the beginning of the study. After six months of follow‐up, 44% (22/50) and 48.3% (29/60) of the participants in the amphotericin B and ILMA groups, respectively, achieved complete cure (RR: 0.91, 95% CI 0.61 to 1.37; N = 110; 1 study, Analysis 47.1).

Secondary outcome: adverse effects

One (1.7%) participant in amphotericin B group presented hypersensitivity, and five (10%) mild pruritus around the lesions. Seven (11.7%) participants in the ILMA group suffered erythema and oedema at the injection site. There were no significant differences in any hypersensitivity rates (RR 3.59, 95% CI 0.15 to 86.19), mild pruritus rates (RR 13.16, 95% CI 0.75 to 232.30), or erythema and oedema rates (RR 0.08, 95% CI 0.00 to 1.36) between groups (N = 110; 1 study, Analysis 47.2).

Primary outcome: percentage of lesions cured after the end of treatment

An RCT from Iran compared topical 15% paromomycin sulphate in 12% MBCL (PR‐MBCL) versus vehicle, twice daily for 30 days (Asilian 2006). Two months after treatment, 41.2% (14/34) and 13.3% (4/30) of the lesions in the PR‐MBCL and placebo groups, respectively, had completely healed (RR 3.09, 95% CI 1.14 to 8.37; N = 64; 1 study Analysis 48.1).

An RCT from Iran compared topical 15% paromomycin in 10% urea (PR‐U) versus vehicle, twice daily for 30 days (Iraji 2005); 12.5% (5/40) and 17.5% (7/40) of the lesions in the respective groups had healed completely one month after treatment (RR 0.71, 95% CI 0.25 to 2.06; N = 80; 1 study, Analysis 49.1).

Primary outcome: percentage of participants with a complete cure after the end of treatment

A pooled analysis of two trials showed no significant differences in cure rates between topical PR‐U and vehicle (RR 1.00; 95% CI 0.86, 1.17; Asilian 1995; Ben Salah 1995; Analysis 50.1). Please see summary of findings Table 2 where we assessed the certainty of evidence as very low, meaning that we are uncertain whether there is much difference in cure rate between paromomycin and vehicle.

An RCT from Iran compared PR‐U versus vehicle, twice daily for 14 days (Asilian 1995). Two and a half months after treatment, 63.5% (80/126) and 63.2% (79/125) of those receiving PR‐U and vehicle, respectively, achieved a complete cure.

An RCT from Tunisia compared PR‐U in soft white paraffin versus vehicle, twice daily for 14 days (Ben Salah 1995). Two and a half months after treatment (day 105), 60.6% (40/66) in each group achieved complete cure.

An RCT from Tunisia compared topical 15% paromomycin plus gentamicin 0.5% versus 15% paromomycin alone versus vehicle, daily for 20 days (Ben Salah 2013). Five and a half months after treatment (day 168), 80% (101/125), 82% (102/125) and 58% (73/125) of participants, respectively, had achieved a complete cure. Paromomycin alone (RR 1.40, 95% CI 1.18 to 1.66, Analysis 51.1) and paromomycin plus gentamicin (RR 1.38, 95% CI 1.17 to 1.64, Analysis 52.1) were more efficacious than vehicle. There was no significant difference between topical 15% paromomycin plus gentamicin 0.5% and 15% paromomycin alone (RR 0.99, 95% CI 0.88 to 1.12; N = 250; 1 study, Analysis 53.1).

Secondary outcome: prevention of scarring

Only Asilian 2006 reported that at the end of the study there was no significant difference in number of deep or disfiguring scars between the PR‐MBCL group (8/34 lesions; 23.5%) and vehicle group (3/10; 10%) (RR 2.35; 95% CI 0.69 to 8.07; N = 64; 1 study, Analysis 48.2). However, we have used the number of lesions originally randomised in presenting the data in this analysis, whereas in the original paper the authors assessed scarring only in lesions that were completely healed at the end of the study (which perhaps makes more sense as a denominator). Both methods of calculating the degree of scarring failed to show any significant differences.

Secondary outcome: adverse effects

Twelve participants between the PR‐U and vehicle groups in Ben Salah 1995 reported a local reaction (inflammation, vesiculation, pain and/or redness); 8 participants from the PR‐U group and 11 from the vehicle group in Asilian 1995 complained about redness, local pain, vesiculation, and inflammation; 3 participants in the PR‐U group in Iraji 2005 reported mild contact dermatitis; and participants in all three groups in Asilian 2006 reported mild and tolerable itch, burning, redness, discharge, oedema, and pain. In Ben Salah 2013, all adverse effects deemed by the investigators to be at least possibly related to a study treatment were reactions of mild or moderate severity at the application site. The paromomycin group reported a little more skin/local reaction (RR 1.42, 95% CI 0.67 to 3.01; N = 713, Analysis 50.2); however, the very low certainty of the evidence means we are not confident about these results (summary of findings Table 2).

Tertiary outcomes: microbiological or histopathological cure of skin lesions

In a pooled analysis of two studies comparing PR‐U versus placebo, there was no significant difference in the number of negative parasitologic smears at a mean follow‐up of 2.5 months (RR 1.03; 95% CI 0.88 to 1.20; Asilian 1995; Ben Salah 1995; Analysis 50.3). The certainty of evidence was very low, meaning we are uncertain whether there was any difference in parasitological cure between the two groups. In another study (Asilian 2006), 64.7% (22/34) in the PR‐MBCL group and 20% (6/30) in the vehicle group were parasitologically free two months after the end of treatment (RR 3.24, 95% CI 1.52 to 6.90; N = 64; 1 study, Analysis 48.3).

Primary outcome: percentage of participants with a complete cure after the end of treatment

An RCT from Iran compared PR‐U ointment, twice per day for a mean duration of 45 days and a maximum duration of 3 months versus ILMA weekly (Faghihi 2003). At less than two months after treatment, the authors reported complete cure of participants in 16.6% (8/48) and 41.7% (20/48) of the PR‐U and ILMA groups, respectively (RR 0.40, 95% CI 0.20 to 0.82; N = 96; 1 study, Analysis 54.1).

Another RCT from Iran compared PR‐U ointment twice a day for 20 days versus ILMA (dose unspecified) every other day for 20 days (Shazad 2005). One week after the end of treatment, 66.7% (20/30) and 60% (18/30) participants of the respective groups achieved complete cure (RR 1.11, 95% CI 0.75 to 1.64; N = 60; 1 study, Analysis 55.1).

Secondary outcomes: duration of remission and percentage of people with treated lesions that recur within six months, one year, two years, and three years

Faghihi 2003 reported a reactivation in 6.3% (3/48) of the participants in both groups at one year after complete recovery, due to lymphatic spread in the PR‐U group and non‐lymphatic spread in the ILMA group (RR 1.00, 95% CI 0.21 to 4.71; N = 96; 1 study, Analysis 54.2). Scarring occurred in 4.2% (2/48) of participants in the PR‐U group and for 8.3% (4/48) in the ILMA group (RR 0.50, 95% CI 0.10 to 2.60; N = 96; 1 study, Analysis 54.3).

Secondary outcome: adverse effects

Regarding adverse effects, Shazad 2005 reported that 1/30 in the PR‐U group and 3/30 participants in the ILMA treatment group withdrew from the study because of cutaneous reactions like erythematosus, urticaria, or lymphadenitis with pain. They were all put on systemic MA and cured thereafter. They did not observe any systemic toxic reaction attributable to the drug. There were no significant differences in adverse effects rates between groups (RR 0.33, 95% CI 0.04 to 3.03; N = 60; 1 study Analysis 55.2).

Primary outcome: percentage of participants with a complete cure after the end of treatment

An RCT from Turkey compared topical PR‐MBCL twice per day for 15 days versus oral ketoconazole 600 mg/d for 30 days (Özgöztasi 1997). One month after the end of treatment the authors reported complete cure of participants in 37.5% (15/40) of the paromomycin group and none in the ketoconazole group (RR 24.95, 95% CI 1.55 to 401.63; N = 72; 1 study, Analysis 56.1).

Secondary outcome: adverse effects

Irritant contact dermatitis was the most common adverse effect described in the PR‐MBCL group. In contrast, the ketoconazole‐treated participants reported no adverse effects.

Tertiary outcomes: microbiological or histopathological cure of skin lesions

The PR‐MBCL and the ketoconazole groups showed incomplete improvement (absence of parasites on culture or smear): just 20% (8/40) and 21.9% (7/32) of participants, respectively, had achieved a microbiological cure at four weeks post‐treatment (RR 0.91, 95% CI 0.37 to 2.25; N = 72; 1 study, Analysis 56.2).

Primary outcome: percentage of lesions cured after the end of treatment

An RCT from Iran compared topical PR‐MBCL twice daily for 28 days versus topical PDT every week for four weeks (Asilian 2006). Two months after treatment, results showed complete cure of lesions in 41.2% (14/34) and 93.5% (29/31) of the PR‐MBCL and PDT groups, respectively (RR 0.44, 95% CI 0.29 to 0.66; N = 65; 1 study, Analysis 57.1).

Secondary outcome: prevention of scarring

At the end of the study, there was no statistical difference (Fisher's exact test P = 0.0558) in the number of deep or disfiguring scars between paromomycin (8/24) and PDT groups (0/31) (RR 15.54, 95% CI 0.39 to 625.57; N = 65; 1 study, Analysis 57.2).

Secondary outcome: adverse effects

Both groups experienced mild and tolerable itch, burning, redness, discharge, oedema, and pain.

Tertiary outcomes: microbiological or histopathological cure of skin lesions

Two months after the end of treatment, 64.7% (22/34) of the lesions in the PR‐MBCL group were parasitologically free, as were all 31 lesions in the PDT group (RR 0.65, 95% CI 0.51 to 0.84; N = 65; 1 study, Analysis 57.3).

Primary outcome: percentage of participants with a complete cure after the end of treatment

An RCT from Iran compared two tubes of 15 g of paromomycin ointment (each tube was enough for two applications per day for 14 days) for a four‐week treatment versus one tube of 15 g of paromomycin ointment for two weeks plus vehicle for two additional weeks (Asilian 2003). Two and a half months after treatment, results showed complete cure of participants in 50% (58/117) and 37% (43/116) of the four‐week and two‐week regimens, respectively. There was no significant difference in cure rates between the four‐week and the two‐week treatment (RR 1.34, 95% CI 0.99 to 1.80; N = 233; 1 study, Analysis 58.1).

Secondary outcome: adverse effects

Participants tolerated the treatment well, and investigators did not observe any adverse effect or adverse reactions to the ointment in either group.

Tertiary outcomes: microbiological or histopathological cure of skin lesions

Three months (105 days) after treatment initiation, there was a small difference in parasitological cure in favour of the four‐week regimen 49/117 (41%) versus 33/116 (28.4%) respectively (RR 1.47, 95% CI 1.03 to 2.11; N = 233; 1 study, Analysis 58.2).

Primary outcome: percentage of lesions with a complete cure after the end of treatment

An RCT from Iraq compared mono doses of IL 2% zinc sulphate solution versus ILSSG 100 mg/mL versus IL 7% HSCS (Sharquie 1997). Investigators left a few lesions on unimportant and unexposed parts of the body as controls. At six weeks after treatment, 94.8% (36/38), 88.5% (31/35), and 85% (34/40) of the lesions, respectively, had healed completely. There were no statistical differences between any comparison: 2% zinc sulphate solution versus ILSSG (RR 1.07, 95% CI 0.93 to 1.23; N = 73; 1 study, Analysis 59.1); 2% zinc sulphate solution versus IL 7% HSCS (RR 1.11, 95% CI 0.96 to 1.30; N = 78; 1 study, Analysis 60.1), or ILSSG versus IL 7% HSCS (RR 1.04, 95% CI 0.87 to 1.24; N = 75; 1 study, Analysis 61.1). In the untreated group, nine participants with 38 lesions were followed up for six weeks, showing no decrease in the size of the lesions and no disappearance of parasites.

Secondary outcome: speed of healing (time taken to be 'cured')

Sharquie 1997 reported that in the zinc sulphate group most lesions were cured by 30 days. In the HSCS and in the ILSSG group, lesions were cured after 30 days.

Secondary outcome: prevention of scarring

In all three groups the scar was minimal or absent after healing, but all participants developed postinflammatory hyperpigmentation. In the control group, some lesions (mainly on the lower limbs) showed signs of infection.

Secondary outcome: adverse effects

Regarding adverse effects, all participants from both groups in the Sharquie 1997 study had pain at the time of the injection.

Primary outcome: percentage of lesions with a complete cure after the end of treatment

An RCT from Iran compared IL zinc sulphate up to six times weekly versus ILMA up to six times weekly (maximum 2 mL) (Firooz 2005). At five weeks after treatment, 22.6% (12/53) and 50.9% (27/53) of the lesions in the respective groups had healed completely (RR 0.44, 95% CI 0.25 to 0.78; N = 106; 1 study, Analysis 62.1). However, baseline characteristics were unbalanced: both mean diameter induration and mean diameter ulceration were higher in the zinc sulphate group (induration: 10.0 mm (standard deviation (SD) 11.4)), and ulceration: 2.7 mm (SD 4.6)) than in the MA group (induration: 2.4 mm (SD 8.7) and ulceration 0.6 mm (SD 3.6)). However, the authors claimed that there was no significant difference between the two groups (P > 0.05; exact p value not reported).

An RCT from Iran compared two double bouts of IL zinc sulphate, delivered at a two‐week interval, versus six weekly bouts of ILMA 60 mg/kg/d (Maleki 2012). At eight weeks after starting treatment, 33.3% (8/24) and 80% (8/10) of participants achieved complete cure in the respective groups (RR 0.42, 95% CI 0.22 to 0.79; N = 34; 1 study, Analysis 63.1).

Primary outcome: percentage of participants with a complete cure after the end of treatment

One RCT from Iran compared IL zinc sulphate with ILMA at a maximum dose of 2 mL (Iraji 2004). In cases with slight to mild improvement, the authors gave another injection after two weeks. The authors reported complete cure in 53% (26/49) and 38% (21/55) of participants in the respective groups at the end of the treatment period. There were no significant differences in cure rates between groups (RR 1.39, 95% CI 0.91 to 2.13; N = 104; 1 study, Analysis 62.2).

Secondary outcome: adverse effects

In Firooz 2005, the most commonly observed adverse effect was pain, found in 25% (18/72) of participants: in 36.1% (13/36) of participants in the zinc sulphate group and 13.9% (5/36) in the ILMA group (RR 2.60, 95% CI 1.03 to 6.54, Analysis 62.3). In the zinc sulphate group, 8.4% (3/36) of participants complained about burning at the injection site. Itching occurred in 8.4% (3/36) and in 25% (9/36), and inflammation in 19.4% (7/36) and 22.2% (8/36) of the cases in the zinc sulphate and ILMA group, respectively. There were no significant differences in other adverse effects rates between groups (Analysis 62.3). Iraji 2004 reported pruritus, erythema, and scaling in the periphery of the injection site in three cases in the ILMA group; IL zinc sulphate was painful, and the severity caused vasovagal shock in two cases. There were no significant differences in skin reactions (RR 7.84, 95% CI 0.42 to 148.08; N = 104; 1 study, Analysis 62.3) or severe pain rates (RR 5.60, 95% CI 0.28 to 113.87; N = 104; 1 study, Analysis 62.3) between groups. In another study the side effects seen in both groups were pain after injection and hyperpigmentation (Maleki 2012). All participants in the zinc sulphate group experienced burning after injection and necrosis of the lesions, and three of these participants also had inflammation and swelling. There were no significant differences in inflammation and swelling rates between groups (RR 3.08, 95% CI 0.17 to 54.71; N = 34; 1 study, Analysis 63.2).

Primary outcome: percentage of participants with a complete cure after the end of treatment

An RCT from Iran compared 5% imiquimod cream three times per week for 28 days plus IMMA 20 mg/kg/d for 14 days versus vehicle plus IMMA at the same dose (Firooz 2006). At 3.5 months after treatment, 44.1% (26/59) and 40% (24/60) of participants in the treatment and control groups, respectively, achieved complete cure (RR 1.10, 95% CI 0.72 to 1.68; N = 119; 1 study, Analysis 64.1).

Secondary outcome: duration of remission and percentage of people with treated lesions that recur within six months, one year, two years, and three years

At four months after treatment, relapse occurred in 1/32 participants available for assessment and treated with imiquimod plus IMMA, and in 3/37 control participants (RR 0.39, 95% CI 0.04 to 3.52; N = 69; 1 study, Analysis 64.2).

Secondary outcome: adverse effects

The only adverse effects related to topical treatment were moderate itch and a burning sensation in three imiquimod‐treated participants. There were no significant differences between groups (RR 7.12, 95% CI 0.38 to 134.84; N = 119; 1 study, Analysis 64.3).

Primary outcome: percentage of lesions with a complete cure after the end of treatment

An RCT from Sri Lanka compared IL HSCS (0.2 mL to 4 mL per lesion and maximum 5 injections) versus ILSSG (maximum 2 mL and 5 injections) (Ranawaka 2010). Average duration of treatment was 8.78 weeks and 5.11 weeks, respectively. At 18 months of follow‐up, 92.2% (86/96) and 100% (136/136) lesions had healed completely in the respective groups (RR 0.87, 95% CI 0.79 to 0.96; N = 147; 1 study, Analysis 65.1). There was no difference in treatment response between therapies with regard to the size, duration, or location (head, trunk, upper, and lower extremities) of the lesions.

Secondary outcome: prevention of scarring

In both groups the scar was minimal or absent after healing, but all participants developed postinflammatory hyperpigmentation.

Secondary outcome: adverse effects

There were no systemic adverse effects with ILSSG or HSCS in Ranawaka 2010. Pain during injection was the only local side effect noted with both therapies. After healing, scarring was minimal, but all participants receiving both treatments had postinflammatory hyperpigmentation, which faded over six to eight months.

Primary outcome: percentage of lesions cured after the end of treatment

An RCT from Iran compared IL HSCS (0.5 mL to 1 mL) with ILMA (0.5 mL to 1 mL) weekly for 6 to 10 weeks (Sadeghian 2006b). At the end of treatment, 25% (9/36) and 33.3% (12/36) lesions had healed in the respective groups (RR 0.75, 95% CI 0.36 to 1.56; N = 72; 1 study, Analysis 66.1).

Secondary outcome: adverse effects

In the HSCS group, there were three cases of sporotrichotic dissemination but with no allergic reactions. In the ILMA group, there were three cases of sporotrichotic dissemination, two satellite lesions, and two allergic reactions including redness, oedema, and severe itch around the lesions. There were no significant differences in sporotrichotic dissemination rates (RR 1.00, 95% CI 0.22 to 4.63; N = 72; 1 study) or allergic reactions rates (RR 0.20, 95% CI 0.01 to 4.03; N = 72; 1 study) between groups (Analysis 66.2).

3.5.3 IL 7% HSCS versus IL ciprofloxacin solution

Primary outcome: percentage of lesions cured after the end of treatment

An RCT from Iraq compared IL 7% HSCS (0.1 mL to 0.5 mL per lesion) with IL ciprofloxacin solution 2 mg/mL (0.1 mL to 0.5 mL per lesion) (Al Hamdi 2010). At two months after treatment, 76.2% (16/21) and 81.5% (22/27) of the lesions had healed in the respective groups. There was no difference in cure rates between IL HSCS and IL ciprofloxacin (RR 1.07, 95% CI 0.79 to 1.44; N = 48; 1 study, Analysis 67.1).

3.5.4 IL 10% HSCS versus IL 15% HSCS versus ILSSG

Primary outcome: percentage of lesions cured after the end of treatment

An RCT from Sri Lanka compared IL 10% HSCS versus IL 15% HSCS versus ILSSG (0.2 mL to 4 mL per lesion and maximum five injections) (Ranawaka 2015). The authors reported that three months after treatment, 93% (268/290), 93.6% (92/98), and 96.3% (226/235) of the lesions in the respective groups had completely healed. There was no difference in cure rates between any comparison: IL 15% HSCS versus IL 10 % HSCS (RR 1.02, 95% CI 0.96 to 1.08; N = 388, Analysis 68.1); ILSSG versus IL 10% HSCS (RR 1.04, 95% CI 1.00 to 1.08; N = 525, Analysis 69.1); and ILSSG versus IL 15% HSCS (RR 1.02, 95% CI 0.97 to 1.08; N = 333; 1 study, Analysis 70.1).

Secondary outcome: speed of healing (time taken to be 'cured')

There was no difference in speed of healing between IL 15% HSCS versus IL 10% HSCS (MD −1.45, 95% CI −4.34 to 1.44 weeks; N = 388; 1 study, Analysis 68.3). Lesions in ILSSG group cured significantly faster than in 10% HSCS group (MD −5.20, 95% CI −6.31 to −4.09 weeks; N = 525, Analysis 69.3) and in IL 15% HSCS group (MD −6.65, 95% CI −9.41 to −3.89 weeks; N = 333, Analysis 70.3).

Secondary outcome: duration of remission and percentage of people with treated lesions that recur within six months, one year, two years, and three years

After six months of follow‐up, the authors described four cases of relapse in 10% HSCS group, four cases in 15% HSCS group and three in the ILSSG group (Ranawaka 2015). There was no significant difference in this outcome in any comparisons: 15% HSCS versus 10% HSCS (RR 2.93, 95% CI 0.75 to 11.50; N = 362; 1 study, Analysis 68.2), ILSSG versus 10% HSCS (RR 0.90 95% CI 0.20 to 3.96, Analysis 69.2), and ILSSG versus 15% HSCS (RR 1.02, 95% CI 0.97 to 1.08, Analysis 70.2).

Secondary outcome: adverse effects

All participants experienced pain during injections, particularly in the 15% HSCS group. All lesions presented postinflammatory hyperpigmentation, which faded over six to eight months. Ulceration and necrosis occurred in 30% (30/98) of the lesions treated with 15% HSCS and in 3.1% (9/290) of the lesions in the 10% HSCS group. There were statistically significant differences in ulceration and necrosis rates between the IL 15% HCS group and the 10% HSCS group (RR 9.86, 95% CI 4.86 to 20.04; N = 388; 1 study, Analysis 68.4) and between the IL 15% HCS group and ILSSG group (RR 145.41, 95% CI 8.98 to 2354.65; N = 333; 1 study, Analysis 70.4), with more events in the IL 15% HCS group.

Primary outcome: percentage of lesions with a complete cure after the end of treatment

An RCT from Syria compared IL IFN‐γ versus ILMA once weekly for five weeks (Harms 1991). At one month after treatment, 3% (1/37) and 76% (29/38) of the lesions had healed completely in the respective groups. The cure rates in the IL IFN‐γ group were significantly lower than in the ILMA group (RR 0.04, 95% CI 0.01 to 0.28; N = 76; 1 study, Analysis 71.1).

Secondary outcome: adverse effects

In the IFN‐γ arm, pain at the injection site of was mild on 68 occasions, moderate on 47, and severe on 38. In the ILMA group it was mild on 55 occasions, moderate on 51, and severe on 40. Other adverse effects included local maculopapular erythema in the ILMA group and headache in the IFN‐γ group.

Tertiary outcomes: microbiological or histopathological cure of skin lesions

Parasitological assessment one month after the end of treatment showed 65% (24/37) and 100% (38/38) of the lesions were parasite‐free in the IFN‐γ and ILMA groups, respectively (RR 0.65, 95% CI 0.51 to 0.83; N = 75; 1 study, Analysis 71.2).

Primary outcome: percentage of participants with a complete cure after the end of treatment

An RCT from Tunisia compared WR279,396 (a third generation aminoglycoside ointment) versus vehicle twice daily for 20 days (Ben Salah 2009). After a six‐month follow‐up, 86% (43/50) and 64% (27/42) of the participants in the respective groups achieved complete cure (RR 1.34, 95% CI 1.04 to 1.72; N = 92, Analysis 72.1).

Secondary outcome: adverse effects

Regarding adverse effects, 30% (n = 15) of participants from the WR279,396 and 24% (n = 10) from the vehicle groups suffered from erythema at the site of application (RR 1.26, 95% CI 0.63 to 2.50; N = 92; 1 study); 14% from both groups (n = 7 and n = 6, respectively) had mild pain within 30 minutes of application (RR 0.98, 95% CI 0.36 to 2.69; N = 92; 1 study); 28% (n = 14) and 21% (n = 9) presented mild increases and decreases in hearing acuity from baseline; 28% (n = 14) and 21% (n = 9) had changed hearing acuity (RR 1.31, 95% CI 0.63 to 2.71; N = 92; 1 study), and there were no deaths reported in either group. See Analysis 72.2.

Primary outcome: percentage of participants with a complete cure after the end of treatment

An RCT compared weekly intralesional metronidazole (2.5 mg to 10 mg = 0.5 mL to 2 mL for each lesion) with weekly ILMA (150 mg to 600 mg = 0.5 mL to 2 mL for each lesion) for up to eight weeks (Mapar 2010). At the end of treatment, 16.6% (3/18) and 72.2% (13/18) of participants in the respective groups achieved complete cure (RR 0.23, 95% CI 0.08 to 0.67; N = 36, Analysis 73.1).

Secondary outcome: adverse effects

Authors did not describe any systemic or local adverse effects with metronidazole, but two participants in the ILMA group suffered local inflammatory reactions with oedema and induration that diminished in about 10 days. There were no significant differences in local inflammatory reactions rates between groups (RR 0.20, 95% CI 0.01 to 3.89; N = 36; 1 study, Analysis 73.2). In both groups the participants reported severe pain at the site of injections, but in the ILMA group it was intolerable.

Primary outcome: percentage of participants with a complete cure after the end of treatment

An RCT from Iran compared topical miltefosine ointment 6% once daily versus ILMA twice a week for up to 28 days (Asilian 2014). At one month after treatment, 81.3% (26/32) and 50.0% (16/32) of the participants in the respective groups achieved complete cure (RR 1.63, 95% CI 1.11 to 2.39; N = 64; 1 study, Analysis 74.1).

Primary outcome: percentage of lesions cured after the end of treatment

An RCT from Iran compared niosomal dapsone 5% gel mask (twice a day) plus ILMA (weekly) versus cryotherapy (every two weeks) plus ILMA (weekly) for up to 16 weeks (Fekri 2015). At 16‐week follow‐up, 82% (29/35) and 86% (33/38) of the lesions had healed in the respective groups (RR 0.95, 95% CI 0.79 to 1.16; N = 73; 1 study, Analysis 75.1).

Primary outcome: percentage of participants with a complete cure after the end of treatment

An RCT from Afghanistan compared 0.045% pharmaceutical chlorite (DAC N‐055) plus bipolar high frequency electrocauterisation for 15 minutes versus 0.045% DAC N‐055 for 15 minutes alone versus ILSSG 0.6 mL for up to 75 days (Stahl 2014). After a 75‐day follow‐up, the authors reported a complete cure in 100% (23/23), 87% (20/23), and 65% (15/23) of the participants in the respective groups. There was no difference between DAC N‐055 plus electrocauterisation versus DAC N‐055 alone (RR 1.15, 95% CI 0.96 to 1.37; N = 46; 1 study, Analysis 76.1). DAC N‐055 plus electrocauterisation was more efficacious than ILSSG (RR 1.52, 95% CI 1.12 to 2.05; N = 46; 1 study, Analysis 77.1), and DAC N‐055 alone was not more efficacious than ILSSG (RR 1.33, 95% CI 0.95 to 1.87; N = 46; 1 study, Analysis 78.1).

Secondary outcome: speed of healing (time taken to be 'cured')

The hazard ratio for DAC N‐055 versus ILSSG was 4.4 (95% CI 2.2 to 8.7) in the per protocol analysis (P < 0.001) and 3.2 (95% CI 1.6 to 6.3) in the intention‐to‐treat analysis (P < 0.001). The lesion closed three to four times faster in the DAC N‐055 group than in the ILSSG group.

Secondary outcome: adverse effects

Regarding adverse effects, four participants developed reulceration of lesions in the DAC N‐055 plus electrocauterisation group, three in the DAC N‐055 alone group, and seven in the ILSSG group. There were no significant differences in reulceration rates between DAC N‐055 plus electrocauterisation versus DAC N‐055 alone (RR 1.33, 95% CI 0.34 to 5.30; N = 46; 1 study, Analysis 76.2). Two participants (8.7%) developed keloids and keloid scars in the DAC N‐055 plus electrocauterisation group.

Primary outcome: percentage of lesions cured after the end of treatment

An RCT from Iran compared 1 mL to 2 mL of Thio‐Ben tincture daily plus cryotherapy (liquid nitrogen (−195°C) fortnightly versus ILMA weekly (dose of 0.5 mL to 2 mL per lesion) plus cryotherapy (Daie Parizi 2015). After three months' follow‐up 91% (20/22) and 92% (23/25) of the lesions had healed completely in the respective groups. There was no difference between Thio‐Ben plus cryotherapy and ILMA plus cryotherapy (RR 0.99, 95% CI 0.83 to 1.18; N = 47; 1 study, Analysis 79.1).

Secondary outcome: speed of healing (time taken to be 'cured')

On average, lesions required the same amount of time to achieve a complete cure: 2.45 months in the Thio‐Ben plus cryotherapy group and 2.41 months in the ILMA plus cryotherapy group (Daie Parizi 2015).

Secondary outcomes: duration of remission and percentage of people with treated lesions that recur within six months, one year, two years, and three years

The rate of relapse was slightly, but not significantly, higher in the Thio‐Ben group 20% (4/22) than in the ILMA group 13% (3/25) (RR 1.52, 95% CI 0.38 to 6.04; N = 47; 1 study, Analysis 79.2).

Secondary outcome: adverse effects

Regarding adverse effects, investigators observed itching and mild erythema in almost all cases with different degrees of severity, and oedema especially after cryotherapy in almost all lesions. Participants from the ILMA plus cryotherapy group experienced pain at the injection site in almost all cases, while three participants reported dizziness and nausea (RR 0.16, 95% CI 0.01 to 2.96; N = 47; 1 study), and one had a hypersensitive reaction (RR 0.38, 95% CI 0.02 to 8.80; N = 47; 1 study, Analysis 79.3). There was poor adherence to treatment particularly among children.

Primary outcome: percentage of lesions cured after the end of treatment

An RCT from Iran compared CO₂ laser applied to the lesion (30 W, continuous) versus IMMA (50 mg/kg/d) for 15 days (this treatment was repeated after 15 days of rest) (Asilian 2004b). At six weeks after treatment, 11% (20/183) and 12% (30/250) of the lesions had healed completely in the respective groups (RR 0.91, 95% CI 0.53 to 1.55; N = 433; 1 study, Analysis 80.1).

Secondary outcomes: speed of healing

The time taken to be cured was one month for the CO₂ laser group and three months for the IMMA group.

Secondary outcome: prevention of scarring

In the laser group, study authors considered most scars to be 'acceptable', except in five cases (4%) in which the lesions were located on the joints or neck, and the resulting scars were raised and hypertrophic.

Secondary outcome: adverse effects

In the laser group, 3% (4/123) of participants experienced hyperpigmentation and persistent redness (RR 12.28, 95% CI 0.67 to 226.62; N = 433; 1 study, Analysis 80.2), and five participants had hypertrophic scarring (RR 0.16, 95% CI 0.01 to 2.96; N = 47; 1 study, Analysis 80.2). In the IMMA group, 9% (22/250) of participants reported myalgia, sensitivity, headache, urticaria, and nausea; these were higher in the IMMA group than in the laser group (RR 0.03, 95% CI 0.00 to 0.50; N = 433; 1 study, Analysis 80.2).

Primary outcome: percentage of lesions cured after the end of treatment

An RCT from Iran compared CO₂ laser (30 W, continuous) applied to the lesion (repeated maximum 3 to 5 times) versus combined cryotherapy (liquid nitrogen 10 s to 25 s) biweekly plus ILMA (0.5 mL to 2 mL per lesion) weekly until complete cure or up to 12 weeks (Shamsi Meymandi 2011). At 12 weeks, 94.7% (90/95) and 77.9% (74/95) of the lesions had healed in the respective groups. CO₂ laser was more efficacious than cryotherapy plus ILMA (RR 1.22, 95% CI 1.08 to 1.37; N = 190; 1 study, Analysis 81.1).

Secondary outcomes: duration of remission and percentage of people with treated lesions that recur within six months, one year, two years, and three years

There was no worsening (increase in size of the lesions) or relapse after the two types of treatment.

Secondary outcome: adverse effects

The authors reported adverse effects to participants (80 participants per group). In the laser group, 25% (n = 20) of participants had hyperpigmentation and trivial scarring, compared to 18.7% (n = 15) in the cryotherapy plus ILMA group (RR 1.33, 95% CI 0.73 to 2.44; N = 190; 1 study); 8.75% (n = 7) and 18.8% (n = 15), respectively, had atrophic scars (RR 0.47, 95% CI 0.20 to 1.09; N = 190; 1 study), and 5% (n = 4) in the laser group only had hypopigmentation plus trivial scarring (RR 9.00, 95% CI 0.49 to 164.88; N = 190; 1 study; Analysis 81.2).

Primary outcome: percentage of participants with a complete cure after the end of treatment

An RCT from Iran compared ablative CO₂ laser (10 ns, frequency: use of 20 kHz, and power: 25 Kw for one session) versus fractional CO₂ laser (energy: 25, one pulse, pass: 1, dot cycle: 6) until complete cure or up to 12 weeks (Nilforoushzadeh 2014a). At six months' follow‐up, 46.7% (28/60) and 76.7% (46/60) of participants in the respective groups achieved a complete cure (RR 0.61, 95% CI 0.45 to 0.83; N = 120; 1 study, Analysis 82.1).

Secondary outcome: adverse effects

Nilforoushzadeh 2014a reported erythema in two participants (3.3%) in the ablative CO₂ laser group and four (6.7%) in the fractional CO₂ laser group (RR 0.50, 95% CI 0.10 to 2.63; N = 120; 1 study, Analysis 82.2).

Primary outcome: percentage of participants with a complete cure after the end of treatment

An RCT from Iran compared trichloroacetic acid (TCA) 50% (wt/vol) applied fortnightly until complete re‐epithelialisation or up to three times versus ILMA (0.5 mL to 2 mL per lesion) weekly until complete re‐epithelialisation of the lesions or up to six weeks (Nilforoushzadeh 2006). At the end of the treatment period, 65% (26/40) and 57.5% (23/40) of participants in the respective groups achieved a complete cure (RR 1.13, 95% CI 0.80 to 1.60; N = 80; 1 study, Analysis 83.1).

Secondary outcomes: duration of remission and percentage of people with treated lesions that recur within six months, one year, two years, and three years

Recurrence occurred in 12.5% (5/40) of the cases in the TCA group and 10% (4/40) in the ILMA group after three months' follow‐up (RR 1.25, 95% CI 0.36 to 4.32; N = 80; 1 study, Analysis 83.2).

Secondary outcome: adverse effects

The observed adverse effects included mild erythema and itch (two cases in the ILMA group), with no significant differences between groups (RR 0.20, 95% CI 0.01 to 4.04; N = 80; 1 study, Analysis 83.3).

Tertiary outcomes: microbiological or histopathological cure of skin lesions

Parasitological assessment at week 6 showed 72.5% (29/40) and 75% (30/40) of the lesions were parasite‐free in the TCA and ILMA groups, respectively. Parasitologic tests were positive at week 6 in 27.5% (11/40) and 25% (10/40) of the cases in the TCA and ILMA groups, respectively. There were no significant differences in parasitologic test rates between groups ((RR 0.97, 95% CI 0.74 to 1.26; participants = 80; studies = 1 Analysis 83.4).

Primary outcome: percentage of participants with a complete cure after the end of treatment

An RCT from Iran compared non‐ablative laser (weekly for four consecutive weeks) plus TCA (applied weekly for up to two weeks) versus ILMA (twice a week up to eight weeks) alone (Nilforoushzadeh 2012). At six months' follow‐up, 42.1% (16/30) and 63.2% (24/30) of the participants in the respective groups achieved a complete cure (RR 0.67, 95% CI 0.46 to 0.97; N = 60, Analysis 84.1).

Primary outcome: percentage of lesions cured after the end of treatment

The authors performed a subgroup analysis according to sex. In the male group, 36.3% (8/22) of the lesions treated with laser plus TCA, and 53.3% (8/15) receiving ILMA, had healed completely at six months (RR 0.68, 99% CI 0.26 to 1.77; N = 37). In females, cure rates in the respective groups were 50% (8/16) and 69.6% (16/23) (RR 0.72, 99% CI 0.34 to 1.50; N = 39; Analysis 84.2).

Primary outcome: percentage of participants with a complete cure after the end of treatment

An RCT from Iran compared TCA (applied weekly for up to eight consecutive weeks until the lesion was frosted) plus ILMA versus fractional laser (fortnightly two sessions) plus ILMA versus ILMA alone twice a week until complete re‐epithelialisation of the lesions or up to eight weeks (Nilforoushzadeh 2013). At six months' follow‐up, 90% (27/30) of the participants in the TCA plus ILMA group, 87% (20/23) in the fractional laser plus ILMA group, and 38.5% (10/26) in the ILMA alone group achieved complete cure. Cure rates were significantly higher in the TCA plus ILMA group compared with ILMA alone (RR 2.34, 95% CI 1.42 to 3.86; N = 56; 1 study, Analysis 85.1). ILMA alone was less efficacious than fractional laser and ILMA (RR 2.26, 95% CI 1.36 to 3.77; N = 49; 1 study, Analysis 86.1). There was no difference in complete cure rates between TCA plus ILMA versus fractional laser plus ILMA (RR 1.03, 95% CI 0.85 to 1.26; N = 53; 1 study, Analysis 87.1).

Secondary outcome: speed of healing (time taken to be 'cured')

Analysis of time to heal data in the Nilforoushzadeh 2013 study only showed significant differences in mean time to heal between TCA plus ILMA versus ILMA alone groups (MD −1.60, 95% CI −2.35 to −0.85 weeks, Analysis 85.2).

Secondary outcome: adverse effects

Nilforoushzadeh 2013 reported adverse effects in 80% (n = 72) of participants. There were five (6.9%) cases of local irritation, two (2.8%) cases of infection, one (1.4%) case of enlargement of lesion, and three (4.2%) cases of satellite lesions. The study did not describe the adverse effects by intervention.

Primary outcome: percentage of participants with a complete cure after the end of treatment

An RCT from Iran compared TCA 50% (applied fortnightly up to frosting the lesion) plus ILMA (twice a week until complete
resolution of the lesions or up to eight weeks) versus ILMA alone (twice a week until complete resolution of the lesions or up to eight weeks) (Nilforoushzadeh 2014b). At the end of the treatment period, 85.7% (78/91) and 80% (76/95) of the participants in the respective groups achieved a complete cure (RR 1.07, 95% CI 0.94 to 1.22; N = 186; 1 study Analysis 88.1). The authors also performed an analysis by the type of lesions (papule, nodule, plaque or ulcerative nodule), but they did not observe any difference between groups.

Primary outcome: percentage of participants with a complete cure after the end of treatment

An RCT from Iran compared a combination of cryotherapy (freezing time was 10 s to 30 s with a thawing interval of 20 s) plus ILMA (after 5 to 10 min of cryotherapy) versus cryotherapy alone versus ILMA monotherapy (0.2 mL to 1.5 mL per session per week) (Salmanpour 2006). Ninety per cent (18/20), 70% (14/20), and 75% (15/20) of the participants in the respective groups had achieved a complete cure; however, authors did not report the time of this assessment. There were no statistical difference in cure rates between any comparisons: cryotherapy plus ILMA versus cryotherapy alone (RR 1.29, 95% CI 0.93 to 1.77; N = 40; 1 study, Analysis 89.1); cryotherapy plus ILMA versus ILMA alone (RR 1.20, 95% CI 0.90 to 1.61; N = 40; 1 study, Analysis 90.1), or cryotherapy alone versus ILMA alone (RR 0.93, 95% CI 0.64 to 1.37; N = 40; 1 study, Analysis 91.1).

An RCT from Iran compared cryotherapy (liquid nitrogen (−195°C) twice to the lesion for 10 s to 15 s, with a thawing interval of 20 s) versus ILMA monotherapy (0.2 mL to 1.5 mL per lesion) weekly for up to six weeks (Layegh 2009). At six months' follow‐up, 58.3% (21/36) and 27.8% (10/36) of the cryotherapy and ILMA group, respectively, achieved a complete cure (RR 2.10, 95% CI 1.16 to 3.81; N = 72; 1 study, Analysis 92.1).

Primary outcome: percentage of lesions cured after the end of treatment

An RCT from Iran compared cryotherapy (liquid nitrogen (−195°C) 10 s to 25 s with a thawing interval of 20 s) plus ILMA (after thawing, 0.5 mL to 2 mL per lesion) versus cryotherapy alone versus ILMA alone (0.5 mL to 2 mL per lesion) fortnightly until complete cure or for up to six weeks (Asilian 2004a). At the end of the treatment period, 80.5% (120/149), 52.2% (120/230) and 52.5% (84/160) of the lesions in the respective groups had healed completely. Cure rates were significantly higher in the cryotherapy plus ILMA group compared with cryotherapy alone (RR 1.54, 95% CI 1.33 to 1.79; N = 379; 1 study, Analysis 93.1) and ILMA alone (RR 1.53, 95% CI 1.30 to 1.81; N = 309; 1 study Analysis 94.1). There were no significant differences in cure rates between ILMA alone and cryotherapy alone groups (RR 0.99, 95% CI 0.82 to 1.20; N = 390; 1 study, Analysis 95.1).

Secondary outcome: speed of healing (time taken to be 'cured')

Only one study reported that none of the cured lesions recurred during the six‐month follow‐up period (Asilian 2004a).

Secondary outcome: adverse effects

Asilian 2004a reported mild adverse side effects, such as postinflammatory hypopigmentation: 5/100 of cases in the combined cryotherapy and ILMA group and 10/230 in the cryotherapy group. There were no significant differences in adverse effects rates between groups (Analysis 93.2; Analysis 94.2; Analysis 95.2). In Salmanpour 2006 there were no serious side effects in any of the treatment groups. However, 35% of the cases in the cryotherapy plus ILMA group, 60% in the cryotherapy alone group, and 20% in the ILMA alone group showed erythema and oedema of the lesions and perilesional area, but these adverse effects rates were not statistically different (Analysis 89.2; Analysis 90.2; Analysis 91.2). The most common adverse effects reported by Layegh 2009 were erythema and oedema at the treated site; these adverse reactions appeared during the initial hours after treatment. Layegh 2009 also described blistering at the treatment site, which became evident one or two days after treatment with a good response to local treatment. Other minor adverse effects are shown in Table 8.

Tertiary outcomes: microbiological or histopathological cure of skin lesions

Only Asilian 2004a reported that all cured lesions showed negative direct smears at the end of treatment and six weeks after treatment.

Primary outcome: percentage of participants with a complete cure after the end of treatment

An RCT from Iran compared a combined triple therapy of cryotherapy (fortnightly for up to 3 sessions) plus 15% paromomycin plus 10% urea cream applied twice a day for 4 weeks plus ILMA (twice a day for four weeks after cryotherapy) versus ILMA monotherapy twice every week until complete healing or for a maximum of six weeks (Nilforoushzadeh 2004). At six weeks after treatment, 84% (68/81) and 75% (57/76) of the participants in the respective groups had achieved complete cure. There were no significant differences in cure rates between groups (RR 1.12, 95% CI 0.95 to 1.31; N = 157; 1 study, Analysis 96.1).

Primary outcome: percentage of lesions cured after the end of treatment

An RCT from Iran compared cryotherapy (once a week) plus 3% salicylic acid cream (twice a day) plus 3% sodium nitrite cream (twice a day) versus cryotherapy plus 3% salicylic acid cream for up to 12 weeks (Jowkar 2012). At the end of the treatment period, 83.3% (30/36) and 74.1% (20/27) of the lesions in the respective groups had healed completely (RR 1.13, 95% CI 0.86 to 1.47; N = 63; 1 study, Analysis 97.1).

Secondary outcome: adverse effects

Jowkar 2012 reported erythema, a burning sensation, and skin irritation in seven participants (19.4%) in the cryotherapy plus salicylic acid plus sodium nitrate group, and in one participant (3.7%) in the cryotherapy plus salicylic acid plus vehicle group. Statistically, this was not a significant difference (RR 5.25, 95% CI 0.69 to 40.17; N = 63; 1 study, Analysis 97.2). See Table 8.

Primary outcome: percentage of lesions cured after the end of treatment

One RCT from Iran compared controlled localised heating using a radiofrequency heat generator (4 MHz, maximum output 90 W weekly) versus ILMA (0.1 mL to 4 mL per lesion) for four consecutive weeks (Sadeghian 2007). Six months after treatment, 80.7% (67/83) and 55.3% (52/94) of the lesions in the respective groups had healed completely. Cure rates were significantly higher in the thermotherapy group compared with ILMA (RR 1.46, 95% CI 1.18 to 1.80; N = 177; 1 study, Analysis 98.1).

We assessed the certainty of evidence as very low.

Primary outcome: percentage of participants with a complete cure after the end of treatment

There were two studies assessing complete cure after the end of treatment (Sadeghian 2007; Safi 2012). Heterogeneity was substantial (P = 0.08; I² = 68%), although both effects are in the same direction. The pooled analysis showed no significant difference in cure rates between thermotherapy and ILMA groups (RR 1.23, 95% CI 0.97 to 1.55; N = 499; 2 studies, Analysis 98.2).

We assessed the certainty of evidence as very low.

Secondary outcomes: duration of remission and percentage of people with treated lesions that recur within six months, one year, two years, and three years

Only the study from Iran reported not finding relapse from lesions with complete response in either group after six months of follow‐up (Sadeghian 2007).

Secondary outcome: prevention of scarring

Sadeghian 2007 reported that although all participants with complete response in both groups had scars, the size of the scars was smaller in the heat‐treated group (15.9 mm before and 11.2 mm after treatment) than in the ILMA‐treated group (15.0 mm before and 14.8 mm after treatment).

Secondary outcome: adverse effects

In Sadeghian 2007, allergic reactions such as erythema, oedema, and pruritus occurred in the ILMA group in four participants with 10 lesions, and there were also four cases of post‐treatment sporotrichotic lesions and three cases of satellite lesions. There was only one case with satellite lesions after treatment in the ILMA group. Safi 2012 reported mild and minimal adverse effects only in the ILMA group.

Participants treated with controlled localised heating reported fewer allergic reactions (RR 0.05, 95% CI 0.00 to 0.76; N = 117, 1 study, Analysis 98.3) but with very low‐certainty evidence.

Primary outcome: percentage of lesions cured after the end of treatment

An RCT from Iraq and Kuwait compared IVSSG (20 mg/kg/d) for 10 doses versus one session of thermotherapy using radiofrequency waves (50 uCTM applied for 30 s) (Aronson 2010). Two months after treatment, 73.3% (63/86) and 59.5% (50/84) of lesions had healed completely in the respective groups. There was no difference in cure rates between groups ((RR 1.23, 95% CI 0.99 to 1.53; participants = 170; studies = 1); Analysis 99.1).

Primary outcome: percentage of participants with a complete cure after the end of treatment

An RCT from Afghanistan compared ILSSG (five injections every five to seven days depending on the lesion size) for up to 29 days versus IMSSG (20 mg/kg/d) daily for 21 days versus thermotherapy using radiofrequency waves (one session of > 1 consecutive application at 50ºC for 30 s depending on lesion size) (Reithinger 2005). Two months after treatment, 47.3% (70/148), 18% (26/144) and 54% (75/139) of the participants in the respective group had achieved a complete cure. Cure rates were significantly higher in the thermotherapy group compared with IMSSG (RR 2.99, 95% CI 2.04 to 4.37; N = 283; 1 study, Analysis 100.1), but there was no difference compared with ILSSG (RR 1.14, 95% CI 0.91 to 1.43; N = 287; 1 study, Analysis 101.1).

An RCT from India compared ILSSG (2 mL to 5 mL per lesion twice a week, for seven injections over 29 days versus thermotherapy using radiofrequency waves (one treatment of two or more consecutive applications at 50ºC for 30 s depending on lesion size) (Bumb 2013). Six months after treatment, 98% and 94% of participants in the respective groups had achieved a complete cure (RR 1.04, 95% CI 0.96 to 1.13; N = 100; 1 study, Analysis 102.1).

Secondary outcome: speed of healing (time taken to be 'cured')

In the Reithinger 2005 study, the speed of healing took a median of 75 days for the ILSSG group, 100 days or more for the IMSSG group, and 53 days for the thermotherapy group (the original paper reported that the time to cure was significantly shorter for participants treated with thermotherapy; P = 0.003, by the log‐rank test). Bumb 2013 described a median time to heal of 11 weeks (95% CI 8 to 12) in the thermotherapy group and 10 weeks (95% CI 8 to 12) in the ILSSG group. In Aronson 2010, time to heal was similar (P = 0.24) in both groups in the analysis using blinded reading of photographs.

Secondary outcome: adverse effects

Reithinger 2005 described secondary infection in 3.7% (5/148) of participants in the ILSSG group, 1.4% (2/144) in the IMSSG group, and 5.7% (8/139) in the thermotherapy group, and there were no statistical differences in either comparison: thermotherapy versus ILSSG (RR 4.14, 99% CI 0.55 to 31.03; N = 283; 1 study, Analysis 100.2) or thermotherapy versus IMSSG (RR 1.70, 99% CI 0.41 to 7.17; N = 287; 1 study, Analysis 101.2). The authors also reported one participant with bradycardia and one an undefined local reaction in the ILSSG group. In the IMSSG group, one participant reported bradycardia, one tachycardia, and one palpitation. In the thermotherapy group, some participants experienced superficial second degree burns. In Bumb 2013, radiofrequency heat treatment (RFHT) was associated with less scarring and hyperpigmentation compared with ILSSG. Aronson 2010 reported four participants (15%) in the thermotherapy group and three (11%) in the ILSSG group suffered serious adverse effects (RR 1.30, 95% CI 0.30 to 5.64; N = 170; 1 study, Analysis 99.2). See Table 9.

Secondary outcome: speed of healing (time taken to be 'cured')

An RCT from Afghanistan compared bipolar high‐frequency electrocauterisation plus daily moist‐wound‐treatment (MWT) with polyacrylate hydrogel including 0.045% DAC N‐055 versus electrocauterisation plus vehicle (Jebran 2014). The speed of healing took a median of 43.15 days for the electrocauterisation plus DAC N‐055 group and 42 days for the electrocauterisation group.

Secondary outcome: adverse effects

Six participants in each group had bacterial and fungal superinfections (8% in the electrocauterisation plus DAC n‐055 group and 9% in the electrocauterisation group; RR 0.85, 95% CI 0.29 to 2.50; N = 135; 1 study, Analysis 103.1), and two participants in electrocauterisation plus DAC n‐055 group and four participants in the electrocauterisation group reported Keloïd formation (5% and 6%, respectively; RR 0.42, 95% CI 0.08 to 2.24; N = 135; 1 study, Analysis 103.1). Other minor adverse effects are shown in Table 9.

Primary outcome: percentage of lesions cured after the end of treatment

An RCT from Iran compared topical PDT every week for four weeks (0% 5‐aminolevulinic acid (5‐ALA) hydrochloride in a water‐in‐oil cream) (Asilian 2006). Lesions irradiated using visible red light at 100 J/cm² per treatment session) with vehicle twice daily also for 28 days. Two months after treatment, 93.5% (29/31) of the lesions in the PDT group and 13.3% (4/30) in the vehicle groups healed completely. Cure rates were significantly higher in the PDT group compared with vehicle (RR 7.02, 95% CI 2.80 to 17.55; N = 61; 1 study, Analysis 104.1).

Secondary outcome: prevention of scarring

At the end of the study, none of the lesions had deep or disfiguring scars in the PDT group. However, 20% (3/30) of the lesions in the vehicle group had deep or disfiguring scars (RR 0.14, 95% CI 0.01 to 2.57; N = 61; 1 study, Analysis 104.2). Both groups had mild and tolerable itch, burning, redness, discharge, oedema, and pain as adverse effects.

Tertiary outcomes: microbiological or histopathological cure of skin lesions

Two months after treatment, parasitological cure rates were significantly higher in the PDT group (100%, 31/31 lesions) compared to placebo (20%, 6/30) (RR 4.69, 95% CI 2.37 to 9.31; N = 61; 1 study, Analysis 104.3).

The same author also compared PDT with topical paromomycin plus methyl benzethonium chloride, which we analyse in section 3.2, 'Topical paromomycin (aminosidine)'.

Primary outcome: percentage of participants with a complete cure after the end of treatment

One RCT from Iran compared mesotherapy (0.05 mL injection of MA in each shot in the depth of 2 mm) versus ILMA (0.1 mL of MA) for up six weeks (Kashani 2010). Three months after treatment, 83.3% (25/30) and 86.7% (26/30) of participants in the respective groups had achieved complete cure (RR 0.96, 95% CI 0.78 to 1.19; N = 60; 1 study, Analysis 105.1).

Secondary outcome: speed of healing (time taken to be 'cured')

The authors did not report significant improvement in ulcer, induration, erythema, or scar size between the two groups. However, the study described faster improvement in participants who received mesotherapy compared to ILMA: ulcerated lesions improved at the rate of 0.27 cm per week (SD 0.14) and 0.15 cm per week (SD 0.72), respectively, with an improvement for erythema of 0.31 cm per week (SD 0.15) and 0.22 cm per week (SD 0.07).

Secondary outcome: adverse effects

Pain severity evaluated by VAS was significantly higher in the ILMA group than in the mesotherapy group (7.67 cm versus 6.06 cm; P = 0.005). Two participants in the mesotherapy group and one in the ILMA group suffered an allergic reaction. There were no significant differences in allergic reaction rates between groups (RR 2.00, 95% CI 0.19 to 20.90; N = 60; 1 study; Analysis 105.2).

Tertiary outcomes: development of cell‐mediated immunity (i.e. positive leishmanin skin test)

Three months after treatment, there were positive Leishmania antibodies in three participants in the mesotherapy group and two participants in the ILMA group. There were no significant differences in adverse effects rates between groups (RR 1.50, 95% CI 0.27 to 8.34; N = 60; 1 study) (Analysis 105.3).

Primary outcome: percentage of participants with a complete cure after the end of treatment

An RCT from Iran compared 5% garlic cream treatment versus vehicle twice a day under occlusion with sterile gauze for three hours, for three weeks (Gholami 2000). At 40 days after treatment, 18.75% (18/96) and 20% (15/75) of the participants in the respective groups had achieved a complete cure. There were no significant differences in cure rates between groups (RR 0.94, 95% CI 0.51 to 1.73; N = 171; 1 study, Analysis 107.1).

Primary outcome: percentage of participants with a complete cure after the end of treatment

An RCT from Iran compared topical herbal extract Z‐HE, covered with a dressing for five consecutive days plus placebo injection (0.5 mL saline) versus IMMA (15 mg/kg/d to 20 mg/kg/d) plus vehicle (petrolatum and charcoal powder) for 20 consecutive days (Zerehsaz 1999). Six weeks after treatment, 74.4% (64/86) and 27.1% (23/85) of participants in the respective groups had achieved complete cure. There was a statistically significant difference in cure rates between topical herbal extract Z‐HE compared with IMMA (RR 2.75, 95% CI 1.90 to 3.98; N = 171; 1 study, Analysis 108.1).

Secondary outcome: adverse effects

Participants in the IMMA reported urticaria and generalised itch.

Primary outcome: percentage of participants with a complete cure after the end of treatment

An RCT from Iran compared topical honey soaked gauze twice a day plus ILMA (weekly) versus ILMA (weekly) for four weeks (Nilforoushzadeh 2007). Results showed that two and a half to three months after treatment, 46% (23/50) and 64% (32/50) of the participants in the respective groups had achieved a complete cure, but with no significant difference between them (RR 0.72, 95% CI 0.50 to 1.04; N = 100; 1 study, Analysis 109.1).

Secondary outcome: speed of healing (time taken to be 'cured')

The mean time taken to be cured after omitting dropouts was 7.04 weeks and 6.3 weeks in the honey plus ILMA and the ILMA groups, respectively.

Primary outcome: percentage of participants with a complete cure after the end of treatment

An RCT from Iran compared topical Cassia fistula fruit gel plus ILMA (0.5 mL to 2 mL) twice a week versus ILMA (0.5 mL to 2 mL) twice a week plus vehicle (Jaffary 2010). Results showed that three months after treatment, compete healing occurred in 67.1% and 41.4% of the participants in the respective groups. There was a statistically significant difference in cure rates in favour of Cassia fistula fruit gel as an adjuvant to ILMA compared with ILMA monotherapy (RR 1.62, 95% CI 1.17 to 2.24; N = 140; 1 study, Analysis 110.1).

Secondary outcome: adverse effects

Nine (12.9%) participants in each group suffered from adverse effects such as itching and erythema (RR 1.00, 95% CI 0.42 to 2.37; N = 140; 1 study, Analysis 110.2).

Primary outcome: percentage of participants with a complete cure after the end of treatment

An RCT from Iran compared topical concentrated boiled Cassia fistula versus topical Cassia fistula hydroalcoholic versus ILMA (0.5 mL to 2 mL), twice a week for four weeks (Jaffary 2014b). Results showed that four months after treatment, 40% (22/55), 36% (20/55), and 65% (36/55) of the participants in the respective groups had achieved complete cure. Efficacy of ILMA was higher than concentrated boiled extract (RR 0.61, 95% CI 0.42 to 0.89; N = 110; 1 study, Analysis 111.1) and hydroalcoholic extract of Cassia fistula (RR 0.56, 95% CI 0.37 to 0.83; N = 110; 1 study, Analysis 112.1), but there was no significant difference between application of concentrated boiled extract and hydroalcoholic extract of Cassia fistula (RR 1.10, 95% CI 0.68 to 1.77; N = 110; 1 study, Analysis 113.1).

Secondary outcome: speed of healing (time taken to be 'cured')

Participants receiving ILMA healed more quickly than those treated with concentrated boiled extract of Cassia fistula (MD −1.80 weeks, 95% CI −3.49 to −0.11; N = 110; 1 study, Analysis 111.2), but there was no difference between concentrated boiled extract of Cassia fistula and hydroalcoholic extract (MD −0.30 weeks, 95% CI −1.70 to 1.10; N = 110; 1 study, Analysis 113.2). There was also no difference between hydroalcoholic extract of Cassia fistula and ILMA (MD −1.50 weeks, 95% CI −3.20 to 0.20; N = 110; 1 study, Analysis 112.2).

Secondary outcome: adverse effects

Three (5.5%) participants in the concentrated boiled extract group and two (3.6%) in the other groups withdrew from the study due to an allergic reaction to the medications. There was no significant difference among these three groups in this regard: boiled extract of Cassia fistula versus ILMA (RR 1.50, 95% CI 0.26 to 8.63; N = 110; 1 study, Analysis 111.3), hydroalcoholic extract of Cassia fistula versus ILMA (RR 1.00, 95% CI 0.15 to 6.85; N = 110; 1 study, Analysis 112.3), or boiled extract of Cassia fistula versus hydroalcoholic extract of Cassia fistula (RR 1.50, 95% CI 0.26 to 8.63; N = 110; 1 study, Analysis 113.3).

Primary outcome: percentage of participants with a complete cure after the end of treatment

An RCT from Iran compared topical gel of 5% Achilles millefolium (twice daily) plus ILMA (weekly injections at 20 mg/kg/d) versus ILMA (weekly injections of 20 mg/kg/d) plus vehicle (twice daily) for four weeks (Jaffary 2014a). Two months after treatment, 53% (16/30) and 40% (12/30) of the participants in the respective groups had achieved a complete cure. There was no difference in cure rates between Achilles millefolium as an adjuvant to ILMA compared with ILMA monotherapy (RR 1.33, 95% CI 0.77 to 2.31; N = 60; 1 study, Analysis 114.1).

Secondary outcome: adverse effects

Eight (26.6%) participants in the Achilles millefolium group reported mild or moderate severe itching and redness, and one experienced severe itching and increasing wound discharge. In the control group, two participants reported mild itching (6.6%) and one, severe itching (3.3%). There were no significant differences in itching rates between groups (RR 3.00, 95% CI 0.90 to 10.01; N = 60; 1 study, Analysis 114.2)

Tertiary outcomes: microbiological or histopathological cure of skin lesions

Six weeks after treatment, 33% of the participants in the Achilles millefolium group and 40% in the control group had parasitological cure (RR 0.83, 95% CI 0.43 to 1.63; N = 60; 1 study, Analysis 114.3).